This invention relates to novel N-Benzhydryl indole compounds useful as intermediates in the synthesis of compounds having pharmacological activity as chemical inhibitors of the activity of various phospholipase enzymes, particularly phospholipase A2 enzymes, and more specifically cytosolic phospholipase A2xcex1.
Leukotrienes and prostaglandins are important mediators of inflammation, each of which classes contributes to the development of an inflammatory response in a different way. Leukotrienes recruit inflammatory cells such as neutrophils to an inflamed site, promote the extravasation of these cells and stimulate release of superoxide and proteases which damage the tissue. Leukotrienes also play a pathophysiological role in the hypersensitivity experienced by asthmatics [See, e.g. B. Samuelson et al., Science, 237:1171-76 (1987)]. Prostaglandins enhance inflammation by increasing blood flow and therefore infiltration of leukocytes to inflamed sites. Prostaglandins also potentiate the pain response induced by stimuli.
Prostaglandins and leukotrienes are unstable and are not stored in cells, but are instead synthesized [W. L. Smith, Biochem. J., 259:315-324 (1989)] from arachidonic acid in response to stimuli. Prostaglandins are produced from arachidonic acid by the action of COX-1 and COX-2 enzymes. Arachidonic acid is also the substrate for the distinct enzyme pathway leading to the production of leukotrienes.
Arachidonic acid which is fed into these two distinct inflammatory pathways is released from the sn-2 position of membrane phospholipids by phospholipase A2 enzymes (hereinafter PLA2). The reaction catalyzed by PLA2 is believed to represent the rate-limiting step in the process of lipid mediated biosynthesis and the production of inflammatory prostaglandins and leukotrienes. When the phospholipid substrate of PLA2 is of the phosphotidyl choline class with an ether linkage in the sn-1 position, the lysophospholipid produced is the immediate precursor of platelet activating factor (hereafter called PAF), another potent mediator of inflammation [S. I. Wasserman, Hospital Practice, 15:49-58 (1988)].
Most anti-inflammatory therapies have focussed on preventing production of either prostglandins or leukotrienes from these distinct pathways, but not on all of them. For example, ibuprofen, aspirin, and indomethacin are all NSAIDs which inhibit the production of prostaglandins by COX-1/COX-2, but have no effect on the inflammatory production of leukotrienes from arachidonic acid in the other pathways. Conversely, zileuton inhibits only the pathway of conversion of arachidonic acid to leukotriense, without affecting the production of prostaglandins. None of these widely-used anti-inflammatory agents affects the production of PAF.
Consequently the direct inhibition of the activity of PLA2 has been suggested as a useful mechanism for a therapeutic agent, i.e., to interfere with the inflammatory response. [See, e.g., J. Chang et al, Biochem. Pharmacol., 36:2429-2436 (1987)].
A family of PLA2 enzymes characterized by the presence of a secretion signal sequenced and ultimately secreted from the cell have been sequenced and structurally defined. These secreted PLA2s have an approximately 14 kD molecular weight and contain seven disulfide bonds which are necessary for activity. These PLA2s are found in large quantities in mammalian pancreas, bee venom, and various snake venom. [See, e.g., references 13-15 in Chang et al, cited above; and E. A. Dennis, Drug Devel. Res., 10:205-220 (1987).] However, the pancreatic enzyme is believed to serve a digestive function and, as such, should not be important in the production of the inflammatory mediators whose production must be tightly regulated.
The primary structure of the first human non-pancreatic PLA2 has been determined. This non-pancreatic PLA2 is found in platelets, synovial fluid, and spleen and is also a secreted enzyme. This enzyme is a member of the aforementioned family. [See, J. J. Seilhamer et al, J. Biol. Chem., 264:5335-5338 (1989); R. M. Kramer et al, J. Biol. Chem., 264:5768-5775 (1989); and A. Kando et al, Biochem. Biophys. Res. Comm., 163:42-48 (1989)]. However, it is doubtful that this enzyme is important in the synthesis of prostaglandins, leukotrienes and PAF, since the non-pancreatic PLA2 is an extracellular protein which would be difficult to regulate, and the next enzymes in the biosynthetic pathways for these compounds are intracellular proteins. Moreover, there is evidence that PLA2 is regulated by protein kinase C and G proteins [R. Burch and J. Axelrod, Proc. Natl. Acad. Sci. U.S.A., 84:6374-6378 (1989)] which are cytosolic proteins which must act on intracellular proteins. It would be impossible for the non-pancreatic PLA2 to function in the cytosol, since the high reduction potential would reduce the disulfide bonds and inactivate the enzyme.
A murine PLA2 has been identified in the murine macrophage cell line, designated RAW 264.7. A specific activity of 2 mols/min/mg, resistant to reducing conditions, was reported to be associated with the approximately 60 kD molecule. However, this protein was not purified to homogeneity. [See, C. C. Leslie et al, Biochem. Biophys. Acta., 963:476492 (1988)]. The references cited above are incorporated by reference herein for information pertaining to the function of the phospholipase enzymes, particularly PLA2.
A cytosolic phospholipase A2 (hereinafter xe2x80x9ccPLA2xe2x80x9d) has also been identified and cloned. See, U.S. Pat. Nos. 5,322,776 and 5,354,677, which are incorporated herein by reference as if fully set forth. The enzyme of these patents is an intracellular PLA2 enzyme, purified from its natural source or otherwise produced in purified form, which functions intracellularly to produce arachidonic acid in response to inflammatory stimuli.
Now that several phospholipase enzymes have been identified, it would be desirable to identify chemical inhibitors of the action of enzymes, which inhibitors could be used to treat inflammatory conditions, particularly where inhibition of production of prostaglandins, leukotrienes and PAF are all desired results. There remains a need in the art for an identification of such anti-inflammatory agents for therapeutic use in a variety of disease states. There also remains a need to identify novel intermediates and methods of synthesizing such therapeutic agents.
This invention comprises intermediate compounds of formula I: 
wherein
R is xe2x80x94(CH2)nxe2x80x94A, xe2x80x94(CH2)nxe2x80x94Sxe2x80x94A, or xe2x80x94(CH2)nxe2x80x94Oxe2x80x94A, where A represents: 
D represents C1-C6 alkyl, C1-C6 alkoxy, xe2x80x94CF3 or xe2x80x94C1-3alkyl-CF3, B and C are each independently selected from the group consisting of phenyl, pyridinyl, pyrimidinyl, furanyl, thiophenyl or pyrrolyl groups, each optionally substituted by from 1 to 3, preferably 1 to 2, substituents selected independently from the group consisting of H, halogen, xe2x80x94CN, xe2x80x94CHO, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94OH, xe2x80x94C1-C6 alkyl, C1-C6 alkoxy, xe2x80x94NH2, xe2x80x94N(C1-C6)2, xe2x80x94NH(C1-C6), xe2x80x94Nxe2x80x94C(O)xe2x80x94(C1-C6), xe2x80x94NO2, or by a 5- or 6-membered heterocyclic or heteroaromatic ring containing 1 or 2 heteroatoms selected from O, N or S;
Rxe2x80x2 is selected from the group consisting of xe2x80x94CH2xe2x80x94OH, xe2x80x94CH2xe2x80x94NHxe2x80x94S(O)2xe2x80x94(CH2)n2-halo, xe2x80x94CH2xe2x80x94NHxe2x80x94S(O)2xe2x80x94CHxe2x95x90CH, xe2x80x94CH2xe2x80x94NH2, or a protected form of xe2x80x94CH2xe2x80x94NH2;
R7 and R8 are independently selected from H, halogen, xe2x80x94CN, xe2x80x94CHO, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94OH, xe2x80x94C1-C6 alkyl, C1-C6 alkoxy, C1-C6 thioalkyl, xe2x80x94NH2, xe2x80x94N(C1-C6)2, xe2x80x94NH(C1-C6), xe2x80x94Nxe2x80x94C(O)xe2x80x94(C1-C6), or xe2x80x94NO2;
R9 represents xe2x80x94CH2)n4xe2x80x94CO2H, an ester form of xe2x80x94(CH2)n4xe2x80x94CO2H, or a pharmaceutically acceptable acid mimic or mimetic;
R10 is selected from H, halogen, xe2x80x94CN, xe2x80x94CHO, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94OH, xe2x80x94C1-C6 alkyl, C1-C6 alkoxy, C1-C6 thioalkyl, xe2x80x94NH2, xe2x80x94N(C1-C6)2, xe2x80x94NH(C1-C6), xe2x80x94Nxe2x80x94C(O)xe2x80x94(C1-C6), or xe2x80x94NO2;
R11 is selected from H, halogen, xe2x80x94CN, xe2x80x94CHO, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94OH, xe2x80x94C1-C6 alkyl, C1-C6 alkoxy, C1-C6 thioalkyl, xe2x80x94NH2, xe2x80x94N(C1-C6)2, xe2x80x94NH(C1-C6), xe2x80x94Nxe2x80x94C(O)xe2x80x94(C1-C6), xe2x80x94NO2, xe2x80x94Nxe2x80x94C(O)xe2x80x94N(C1-C3 alkyl)2 , xe2x80x94Nxe2x80x94C(O)xe2x80x94NH(C1-C3 alkyl), xe2x80x94Nxe2x80x94C(O)xe2x80x94Oxe2x80x94(C1-C3 alkyl), xe2x80x94SO2xe2x80x94C1-C6 alkyl, xe2x80x94Sxe2x80x94C3-C6 cycloalkyl, xe2x80x94Sxe2x80x94CH2xe2x80x94C3-C6 cycloalkyl, xe2x80x94SO2xe2x80x94C3xe2x80x94C6 cycloalkyl, , xe2x80x94SO2xe2x80x94CH2xe2x80x94C3xe2x80x94C6 cycloalkyl, C3-C6 cycloalkyl, xe2x80x94CH2xe2x80x94C3xe2x80x94C6 cycloalkyl, xe2x80x94Oxe2x80x94C3xe2x80x94C6 cycloalkyl, , xe2x80x94Oxe2x80x94CH2xe2x80x94C3xe2x80x94C6 cycloalkyl, phenyl, benzyl, benzyloxy, morpholino or other heterocycles such as pyrrolidino, piperidine, piperizine, furan, thiophene, imidazole, tetrazole, pyrazine, pyrazolone, pyrazole, imidazole, oxazole or isoxazole, the rings of each of these groups each being optionally substituted by from 1 to 3 substituents selected from the group of H, halogen, xe2x80x94CN, xe2x80x94CHO, xe2x80x94CF3, xe2x80x94OH, xe2x80x94C1-C6 alkyl, C1-C6 alkoxy, xe2x80x94NH2, xe2x80x94N(C1-C6)2, xe2x80x94NH(C1-C6), xe2x80x94Nxe2x80x94C(O)xe2x80x94(C1-C6), xe2x80x94NO2, xe2x80x94SO2(C1-C3 alkyl), xe2x80x94SO2NH(C1-C3 alkyl), xe2x80x94SO2N(C1-C3 alkyl)2, or OCF3;
n is an integer from 0 to 3;
n1 is an integer from 0 to 3;
n2 is an integer from 0 to 3
n3 is an integer from 0 to 3;
n4 is an integer from 0 to 2; and,
X is a linking group selected from the group consisting of xe2x80x94Oxe2x80x94, xe2x80x94CH2xe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94NHxe2x80x94, and xe2x80x94N(C1-C6-alkyl)xe2x80x94.
A preferred embodiment of the invention comprises benzhydryl indole compounds of formula II: 
wherein:
Rxe2x80x2, R7-11, X, n1, n2 and n4 are as defined above; and,
R1, R2, R3, R4, R5 and R6 are each independently selected from H, halogen, xe2x80x94CN, xe2x80x94CHO, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94OH, xe2x80x94C1-C6 alkyl, C1-C6 alkoxy, xe2x80x94NH2, xe2x80x94N(C1-C6)2, xe2x80x94NH(C1-C6), xe2x80x94Nxe2x80x94C(O)xe2x80x94(C1-C6), xe2x80x94NO2, or a 5- or 6-membered heterocyclic or heteroaromatic ring containing 1 or 2 heteroatoms selected from O, N or S.
The term halogen or halo is used in this specification to refer to F, Cl, Br and I. Preferred halogen atoms in the Rxe2x80x2 group xe2x80x94CH2xe2x80x94NHxe2x80x94S(O)2xe2x80x94(CH2)n2-halo include bromine and chlorine.
Preferred ester forms of the compounds of formula II wherein R9 is xe2x80x94(CH2)n4xe2x80x94CO2H, are the C1-C8 alkyl esters, including straight, branched and cyclic alkyl groups, and benzyl esters.
Commercially available and art recognized amine protecting groups are useful to form the protected forms of the CH2)n1xe2x80x94CH2xe2x80x94NH2 groups described above. These include those represented by the formulae below, wherein the number of carbon atoms in the chain are merely presented for illustration and do not limit the number of carbon atoms in the corresponding carbon chains of this invention. 
Other non-limiting examples of amine protecting groups useful with the compounds of this invention include, but are not limited to, the following:
1) amide types such as formyl, acetyl, chloroacetyl, trichloroacetyl, o-nitrophenylacetyl, o-nitrophenoxyacetyl, trifluoroacetyl, acetoacetyl, phthalyl, and p-toluenesulfonyl;
2) aromatic carbamate types such as benzyloxycarbonyl (CBZ), and benzyl substituted one or more time with with alkyl, cyano, nitro, chloro, fluoro, bromo, and methoxy; diphenylmethyl, 1-(p-biphenyl)-1-methylethyl, 9-fluorenylmethyl (Fmoc), 2-phenylethyl, and cinnamyl groups;
3) aliphatic carbamate types such as tert-butyloxycarbonyl (Boc), ethyl, diisopropylmethyl, allyl, vinyl, t-amyl, diisopropylmethyl, and isobutyl;
4) cyclic alkyl carbamate types such as cyclopentyl, cyclohexyl, cyclopropylmethyl, and adamantyl;
5) alkyl type amine protecting groups such as triphenylmethyl (trityl) and benzyl;
6) trialkylsilane groups such as trimethylsilane, triethylsilane, triisopropylsilane, tri-t-butylsilane, triphenylsilane, tritolylsilane, trimesitylsilane, methyidiphenylsilane, dinaphthylmethylsilane, bis(diphenyl)methylsilane, etc.; and
7) thiol containing types of protecting groups, such as phenylthiocarbonyl and dithiasuccinoyl protecting groups.
Other preferred amine protecting groups for use with this invention are ethoxycarbonyl groups, acyl groups, including 4-chlorobutyryl isobutyryl, o-nitrocinnamoyl, picolinoyl, acylisothiocyanate, aminocaproyl, benzoyl and the like, and acyloxy groups including methoxycarbonyl, 9-fluorenylmethoxycarbonyl, 2,2,2-trifluoroethoxycarbonyl, 2-trimethylsilylethxoy carbonyl, vinyloxycarbonyl, allyloxycarbonyl, 1,1-dimethylpropynyloxycarbonyl, p-nitrobenzyloxycarbony, 2,4-dichlorobenzyloxycarbonyl, and the like.
Pharmaceutically acceptable acid mimics or mimetics which may appear at R9 include those selected from the formulae: 
wherein Ra is selected from xe2x80x94CF3, xe2x80x94CH3, phenyl, or benzyl, with the phenyl or benzyl groups being optionally substituted by from 1 to 3 groups selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 thioalkyl, xe2x80x94CF3, halogen, xe2x80x94OH, or xe2x80x94COOH; Rb is selected from xe2x80x94CF3, xe2x80x94CH3, xe2x80x94NH2, phenyl, or benzyl, with the phenyl or benzyl groups being optionally substituted by from 1 to 3 groups selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 thioalkyl, xe2x80x94CF3, halogen, xe2x80x94OH, or xe2x80x94COOH; and Rc is selected from xe2x80x94CF3 or C1-C6 alkyl.
Another preferred embodiment of the compounds of this invention is represented by formula III: 
wherein each of the variables R1 through R11, X and n4 are as defined above. A particularly preferred embodiment are compounds of formula IlI in which R1 through R6 are each hydrogen.
Another preferred embodiment of the compounds of this invention are those of formula IV: 
wherein each of the variables R1 through R11, and X are as defined above.
A particularly preferred embodiment of the of this invention are compounds of formula IV in which R1 through R6 are each hydrogen.
Among the most preferred compounds of the present invention are the compounds below which are designated Intermediates No. 1, 2 and 3. An illustrative method for making these intermediates is also shown. These examples of highly preferred compounds and methods should not be construed as limiting the scope of the invention.
Intermediate No. 1
4{2-[2-(2-Amino-ethyl)-1-benzyhydryl-5-chloro-1H-indol-3-yl]-ethanesulfonyl}-benzoic acid methyl ester. 
Step 1: 2-Bromo-4-chloroaniline(1.0 eq) was dissolved in CH2Cl2 (0.25M), then triethylamine and triflouroacetyl anhydride(1.1 eq each) were added. The resulting mixture was stirred at room temperature for 1 hour. Solvent was then stripped-off from the reaction mixture, and the residue was purified by flash chromatography with dichloromethane as eluent to give the described product in 97% yield. m/z(Mxe2x88x92H)300.0.
Step 2: N-(2-Bromo4-chlorophenyl)-2,2,2-trifluoroacetamide(step 1, 1.0 eq) was mixed with 3-butyn-1-ol(2.0 eq), dichlorobis(triphenylphosphine)palladium(lI) (2.5% eq), triethylamine(3.0 eq), Cul(5% eq) in DMF(0.2M) in a sealed vessel under N2 and heated to 120xc2x0 C. for 4 hours. The reaction mixture was then diluted with ethyl acetate, washed with brine and dried over Na2SO4. Furthermore, evaporate the solvent and the residue was purified by flash column chromatography with 2% MeOH/CH2Cl2 to give the described 2-(5-Chloro-1H-indol-2-yl)ethanol in 67% yield. m/z(Mxe2x88x92H)194.09
Step 3: 2-(5-chloro-1H-indol-2-yl)ethanol (1 eq) was added to a solution (under N2) containing tert-Butyldiphenylchlorosilane (1.2 eq), imidazole (2.5 eq), and DMF (1.8M). The reaction was stirred overnight. Quenched with NaHCO3 (aq) and extracted with a Et2O/EtOAc mixture. The organic layer was washed with water and brine and dried over sodium sulfate. Purified with silica gel column and 1:4 Hexane/CH2Cl2 as eluent. Obtained 2-({[tert-butyl(diphenyl)silyl]oxy}ethyl)-5-chloro-1H-indole (yellow oil) in 98% yield.
Step 4: Methyl 4-[(2-oxoethyl)sulfanyl]benzoate (3.7 eq) was added to a solution containing 2-({[tert-butyl(diphenyl)silyl]oxy}ethyl)-5-chloro-1H-indole (1 eq), TFA (3 eq), and 1,2-dichloroethane (0.1M) at 0xc2x0 C. under N2. Then Et3SiH (12 eq) was added and the reaction was allowed to return to room temperature and stirred overnight. Quenched reaction with NaHCO3(aq) and extracted with EtOAc and washed with brine and dried over sodium sulfate. Purified with silica gel column and 1:5 EtOAc/Hexane as eluent. Obtained methyl 4-({2-[2-(2{[tert-butyl(diphenyl)silyl]oxy}ethyl)-5-chloro-1H-indol-3-yl]ethyl}sulfanyl)benzoate (yellow solid) in 79% yield.
Step 5: Methyl 4-({2-[2-(2-{[tert-butyl(diphenyl)silyl]oxy}ethyl)-5-chloro-1H-indol-3-yl]ethyl}sulfanyl)benzoate (1 eq) was added to a suspension of NaH (1.1 eq) in DMF (0.37M) at 0xc2x0 C. under N2. After 30 minutes Ph2CHBr (1.8 eq) was added and the reaction was warmed to room temperature. After 3 hours the reaction was quenched with NH4Cl(aq) and extracted with EtOAc/Et2O mix and washed with water and brine and dried over sodium sulfate. Purified with silica gel column and 1:5 EtOAc/Hexane. Obtained methyl 3-[4-({2-[1-benzhydryl-2-(2-{[tert-butyl(diphenyl)silyl]oxy}ethyl)-5-chloro-1H-indol-3-yl]ethyl}sulfanyl)phenyl]benzoate (yellow gum) in 65% yield.
Step 6: NMO (4 eq) was added to a solution/suspension containing methyl 3-[4-({2-[1-benzhydryl-2-(2-{[tert-butyl(diphenyl)silyl]oxy}ethyl)-5-chloro-1H-indol-3-yl]ethyl}sulfanyl)phenyl]benzoate (1 eq), ACN (0.1M), and molecular sieves (1 g/mmole of benzoate) under N2. After 10 minutes TPAP (0.12 eq) was added and the mixture was heated to 40xc2x0 C. After 1.5 hours the reaction was cooled and filtered and the filtrate was collected. Purified with silica gel column and 1:5 EtOAc/Hexane. Obtained methyl 3-[4-({2-[1-benzhydryl-2-(2-{[tert-butyl(diphenyl)silyl]oxy}ethyl)-5-chloro-1H-indol-3-yl]ethyl}sulfonyl)phenyl]benzoate (white solid) in 71% yield.
Step 7: Tetrabutylammonium fluoride (1M in THF) (1.2 eq) was added to a solution of methyl 3-[4-({2-[1-benzhydryl-2-(2-{[tert-butyl(diphenyl)silyl]oxy}ethyl)-5-chloro-1H-indol-3-yl]ethyl}sulfonyl)phenyl]benzoate (1 eq) and THF (0.1M) at 0xc2x0 C. under N2. Warmed reaction to room temperature and after 1 hour quenched with NH4Cl(aq). Extracted with EtOAc and washed with brine and dried over sodium sulfate. Purified with silica gel column and 1:9 EtOAc/CH2Cl2. Obtained methyl 3-[4-({2-[1-benzhydryl-5-chloro-2-(2-hydroxyethyl)-1H-indol-3-yl]ethyl}sulfonyl)phenyl]benzoate (white solid) in 86% yield.
Step 8: CH3SO2Cl (2 eq) and Et3N (2.5 eq) were added to a solution of methyl 3-[4-({2-[1-benzhydryl-5-chloro-2-(2-hydroxyethyl)-1H-indol-3-yl]ethyl}sulfonyl)phenyl] benzoate (1 eq) in CH2Cl2 (0.02M) at 0xc2x0 C. under N2. After 1 hour the reaction was warmed to room temperature. After an additional hour water was added and extracted with CH2Cl2 and washed with brine and dried over sodium sulfate. Removed solvent to obtain methyl 3-(4-{[2-(1-benzhydryl-5-chloro-2-{2-[(methylsulfonyl)oxy]ethyl)1H-indol-3-yl)ethyl]sulfonyl}phenyl)benzoate (light-yellow solid) in 99% yield.
Step 9: Methyl 3-(4-{[2-(1-benzhydryl-5-chloro-2-{2-[(methylsulfonyl)oxy]ethyl}-1 H-indol-3-yl)ethyl]sulfonyl}phenyl)benzoate (1 eq), sodium azide (5 eq), and DMF (0.05M) were placed together under N2 and heated to 60xc2x0 C. After 1 hour the reaction was cooled and water was added. Extracted with EtOAc/Et2O mix and washed with water and brine and dried over sodium sulfate. Removed solvent to obtain methyl 3-[4-({2-[2-(2-azidoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethyl}sulfonyl)phenyl]benzoate (light-yellow solid) in 99% yield.
Step 10: Methyl 3-[4-({2-[2-(2-azidoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethyl}sulfonyl)phenyl]benzoate (1 eq), PPh3 (2 eq), and THF (0.1M) were placed together under N2 and stirred overnight. Water (1 mL /1 mmole benzoate) was added and reaction was again stirred overnight. The solution was concentrated and purified with silica gel column and 3:1 EtOAc/Hexane followed by 5% MeOH in CH2Cl2. Obtained methyl 3-[4-({2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethyl}sulfonyl)phenyl]benzoate (light-yellow solid) in 99% yield.
Synthesis of Intermediate No. 1 is also described below in Example 135, Steps 1-8. This intermediate could also be synthesized by method K or method M, which are set forth below.
Intermediate No. 2
4-{2-[2-(2-Amino-ethyl)-1-benzyhydryl-5-chloro-1H-indol-3-yl]-ethoxy}-benzoic acid methyl ester. 
Step 1: To 4-hydroxy-benzoic acid methyl ester (1.0 eq) in DMF (0.83 M) was added K2CO3 (2.0 eq) followed by 2-bromo-1,1-diethoxy-ethane and the reaction mixture was stirred at 110xc2x0 C. for 2 days. TLC showed a new spot. The reaction mixture was diluted with ethyl acetate, washed with 1 N NaOH, water, and brine, dried over sodium sulfate, and solvent was removed to afford desired product in 84% yield. This material was used in the next step without further purification.
Step 2: To the above product (1.0 eq) and 5-chloro-2-methyl indole (1.0 eq) in CH2Cl2 (0.12 M) was added triethylsilane (3.0 eq) followed by trifluoroacetic acid (3.0 eq). After being stirred overnight at room temperature, added water and trifluroacetic acid (1.0 eq) to the reaction mixture, stirred at room temperature for two days, diluted with CH2Cl2, washed with 1N NaOH, water, brine, dried over sodium sulfate. Trituration of the material with CH2Cl2 and hexanes afforded the C3 alkylated indole in 92% yield
Step 3: To the indole from above (1.0 eq) in DMF (0.36 M) at 25xc2x0 C. was added NaH (1.2 eq, 60% dispersion in oil), and the brown solution was stirred at 0 to xe2x88x925xc2x0 C. for 1 h and then compound bromodiphenylmethane was added (1.1 eq), and then the reaction mixture was stirred overnight. It was then quenched with water, diluted with ethyl acetate, washed with water and brine, dried over sodium sulfate and purified by column chromatography to yield 72% of the desired product.
Step 4: To the N-alkylated indole from above (1.0 eq) in CCl4 (0.2 M) was added N-bromosuccinimide (2.0 eq) and a catalytic amount of benzoyl peroxide. The solution was heated to reflux for 3 h, cooled to 25xc2x0 C., filtered, and the solid was washed with CCl4. The filtrate was concentrated to a foam, which was dried. The foam was dissolved in acetone, and Ag2CO3 (1.1 eq.) was added followed by water and the reaction mixture was stirred overnight at room temperature. It was filtered and washed with acetone. The filtrate was concentrated to a residue, to which was added water. This mixture was extracted with ethyl acetate, washed with brine, dried over sodium sulfate and then chromatographic purification on the residue gave the desired product in 85% yield. Alternatively the dibromide from the reaction with NBS could be poured into DMSO (10-20% concentration by weight) stirred for 30 minutes at room temperature. When the reaction was deemed complete it was poured into water and the resulting precipitate was isolated by filtration, the cake was washed with water and dried to yield an essentially quantitative yield.
Step 5: To the above aldehyde (1.0 equiv) in CH3NO2 (0.2 M) was added ammonium acetate (4 equiv) and the resulting mixture was heated to reflux for 4 h. The reaction mixture was then diluted with EtOAc and washed with brine. The aqueous phase was extracted with EtOAc. The combined organic extracts were washed with brine, dried over sodium sulfate, and concentrated until an orange crystalline solid precipitated. The mixture was refrigerated overnight and the nitroolefin (76% yield) was collected by filtration. Evaporation of the solution phase and purification of the residue by column chromatography (gradient elution 100% toluenexe2x86x921% EtOAc-toluene) afforded an additional amount of the nitroolefin (23% yield).
Step 6: Zinc dust (20 equiv) was suspended in 5% aqueous HCl solution (8 M Zn/5% HCl). To this mixture was added HgCl2 (0.28 equiv). The mixture was shaken for 10 min, the aqueous phase was decanted and replaced with fresh 5% HCl, and again the mixture was shaken for 5 min and the aqueous phase was removed. The zinc-mercury amalgam thus generated was then added to a mixture of the nitroolefin (1.0 equiv) and conc. HCl (80 equiv) in THF (0.04 M nitroolefin/THF). The mixture was maintained at a gentle reflux for 1 h. The formation of product was followed by TLC analysis. The mixture was cooled to room temperature and the solids were removed by filtration through Celite. Conc. NH4OH was added to the solution phase and the mixture was concentrated on the rotary evaporator. The residue was dissolved in CH2Cl2 and conc. NH4OH. The aqueous phase was extracted with CH2Cl2, and the organic phase was washed with brine, dried over sodium sulfate, and concentrated. Purification by column chromatography afforded the desired product (65% yield).
Synthesis of Intermediate No. 2 is also described in Example 1, Steps 1-6. This intermediate could also be synthesized using methods K, L, or M, as set forth below.
Intermediate No. 3
4-{3-[2-(2-Amino-ethyl)-1-benzyhydryl-5-chloro-1H-indol-3-yl]-propyl}-benzoic acid methyl ester 
Step 1: A mixture of methyl-4-iodobenzoate (5.3 g, 20.2 mmol), allyl alcohol (1.78 g, 30.3 mmol), NaHCO3 (4.24 g, 50.5 mmol), Pd(OAc)2 (0.14 g, 0.60 mmol), (n-Bu)4NBr (6.55 g, 20.2 mmol) and 4-A molecular Sieves (4.1 g) in anhydrous DMF (69 mL) was stirred at room temperature for 4 days. The reaction mixture was filtered through celite and the filtrate poured onto water and extracted with EtOAc. Organic layer was washed with brine, dried (Na2SO4), and concentrated under vaccum. Flash chromatography (silica gel, 10-20% EtOAc-hexanes) gave 2.11 g (85% based on the recovered starting material) of the desired 4-(3-Oxo-propyl)-benzoic acid methyl ester as a clear oil.
Step 2: To a solution of 5-chloro-2-methylindole (0.86 g, 5.2 mmol) and 4-(3-Oxo-propyl)-benzoic acid methyl ester (1.0 g, 5.2 mmol) in methylene chloride (5 mL), was added TFA (1.78 g, 15.6 mmol), followed by triethylsilane (1.81 g, 15.6 mmol). The reaction mixture was stirred overnight, quenched with sat. NaHCO3 solution (50 mL), and the organic layer was washed with sat. NaHCO3 solution, water, brine, and dried (Na2SO4). Solvent was removed under reduced pressure, and the residue was purified by flash column chromatography with 10-20% EtOAc/hexanes to yield the desired product in 94% (1.67 g) yield.
Step 3: To a solution of the product from step 2 (1.66 g, 4.86 mmol) in DMF (20 mL) was added NaH (60% in mineral oil, 0.24 g, 5.83 mmol) under N2 atmosphere. The mixture was stirred for 1 h at room temperature, followed by the dropwise addition of benzhydryl bromide (1.8 g, 7.29 mmol) in DMF (5 mL). This reaction mixture was stirred overnight at room temperature. Water (50 mL) was added to reaction mixture, it was extracted with EtOAc, washed with brine, dried (Na2SO4), and concentrated under reduced pressure to a brown syrup, which was purified by silica-gel chromatography using 10% EtOAc/hexanes as eluent to isolate 4 as a white solid in 59% (1.47 g) yield.
Step 4: The product from above (1.46 g, 2.87 mmol) was dissolved in CCl4 (14.5 mL), followed by the addition of NBS (1.02 g, 5.73 mmol) and benzoyl peroxide (2 mg). The reaction mixture was heated to reflux for 1 h (until all the starting material disappeared). This mixture was cooled to room temperature, filtered and the solid was washed with CCl4. The filtrate was evaporated to a brown residue, which was dissolved in acetone (40 mL) and water (4 mL), Ag2CO3 (1.75 g, 3.16 mmol) was then added to this solution and after being stirred overnight at room temperature, it was filtered through celite, the solvent was evaporated under reduced pressure, and water was added to the residue. It was extracted with EtOAc, washed with brine, dried (Na2SO4), and evaporated to a syrup, which was purified by 10% EtOAc/hexanes to isolate the 2-formyl indole (1.13 g) in 75% yield. Alternatively the dibromide from the reaction with NBS could be poured into DMSO (10-20% concentration by weight) and stirred for 30 minutes at room temperature. When the reaction was deemed complete it was poured into water and the resulting precipitate was isolated by filtration, the cake was washed with water and dried to yield an essentially quantitative yield.
Step 5: To a solution of the 2 formyl indole from above (0.52 g, 1 mmol) in CH3NO2 (6.2 mL) was added NH4OAC (0.077 g, 1 mmol), the mixture was heated to reflux for 1 h, NH4 OAc (0.077 g, 1 mmol) was then added, heating at reflux was continued for an additional 1 h, NH4Oac (0.077 g, 1 mmol) was added again and the heating continued for further 1 h. The reaction mixture was allowed to attain room temperature, EtOAc (50 mL) was added, followed by the addition of 100 mL water. The aqueous layer was extracted with EtOAc, and the combined organic layers were washed with brine, dried (Na2SO4), and evaporated to a yellow foam, which was subjected to chromatographic purification using 10% EtOAc/hexanes as an eluent to yield 6 as a yellow foam in 68% yield (0.38 g).
Step 6 :Zn(Hg) was made by adding HgCl2 ( 3.4 g, 7.2 mmol) to a mixture of Zn-dust (34.68 g, 530.35 mmol) and 5% HCl (38 mL) in a 100 mL beaker, this mixture was stirred vigorously for 10 min. Aqueous phase was decanted and added 38 mL of 5% HCl again and the mixture was stirred for 10 min. Aqueous phase was decanted. This solid was added to the vinyl nitro compound 6 (15 g, 26.57 mmol) in THF (660 mL) and conc. HCl (64.5 mL). This mixture was stirred at room temperature for 1 h, then at reflux for 15 min. The reaction mixture was cooled to room temperature and filtered through celite. Aq. NH4OH solution (200 mL) was added to the filtrate, stirred for 15 min and THF was removed under reduced pressure. The aqueous layer was extracted with CH2Cl2, combined organic layer was washed with brine, dried (Na2SO4) and concentrated to a brown foam, which was purified by column chromatography by eluting the column with CHCl3 in the beginning to remove non-polar impurities then with 2% MeOH/CHCl3 to isolate the desired amine in 46% yield (6.1 g).
Synthesis of Intermediate No. 3 is also described below in Example 42, Steps 1-6. This intermediate could also be formed using Methods J, K, or M, as set forth below.
Intermediate No. 4
4-{2-[2-(2-Amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-ethylamino}-benzoic acid methyl ester 
Step 1: To a solution of 4-chloro-2-iodoaniline (16.5 g, 65.1 mmol) in DMF (250 mL) at rt were added xcex1-bromodiphenylmethane (21.5 g, 84.6 mmol) and iPr2NEt (23 mL, 130 mmol) and the reaction mixture was heated at 45xc2x0 C. overnight. After the volatile was removed under reduced pressure, the residue was dissolved in EtOAc, washed with water (3xc3x97) and brine and dried over MgSO4. Purification on SiO2 column chromoatography (hexanes to 5% EtOAc/hexanes) gave the desired Benzhydryl-(4-chloro-2-iodo-phenyl)-amine (26.1 g, 97% yield) as a yellowish solid.
Step 2: A mixture of benzhydryl-(4-chloro-2-iodo-phenyl)-amine (26.1 g, 62.2 mmol), PdCl2(PPh3)2 (1.90 g, 2.67 mmol), Cul (1.2 g, 6.2 mmol), 3-butyn-1-ol, and Et3N (120 mL) was stirred at 45xc2x0 C. for 20 hours. The reaction mixture was filtered through celite and rinsed with EtOAc. The filtrate was concentrated, redissolved in EtOAc, washed with water (3xc3x97) and brine, and dried over MgSO4. The crude 4-[2-(Benzhydryl-amino)-5-chloro-phenyl]-but-3-yn-1-ol (25.5 g) was used in the next step directly without further purification.
Step 3: A solution of the crude 4-[2-(benzhydryl-amino)-5-chloro-phenyl]-but-3-yn-1-ol (25.5 g) and Cul (2.7 g, 14.1 mmol) in DMF (200 mL) was heated at 125xc2x0 C. for 24 hours. The reaction mixture was filtered through celite and rinsed with EtOAc. The filtrate was concentrated, redissolved in EtOAc, washed with water (3xc3x97) and brine, and dried over MgSO4. Silica gel column chromatography (30% EtOAc/hexanes) yielded the desired 2-(1-Benzhydryl-5-chloro-1H-indol-2-yl)-ethanol as a yellow solid (14.5 g, 73% over 2 steps).
Step 4: To a solution of 2-(1-benzhydryl-5-chloro-1H-indol-2-yl)-ethanol (15.3 g, 42.3 mmol) in CH2Cl2 (190 mL) at 0xc2x0 C. were added imidazole (3.72 g, 55.0 mmol) and TBDPSCl (13.2 mL, 50.8 mmol). After stirring at the same temperature for 1.5 hours, the reaction mixture was washed with cold water (3xc3x97) and brine, and dried over MgSO4. The crude silyl ether was used in the next step directly without further purification.
Step 5: To a solution of the crude silyl ether in Et2O (200 mL) at 0xc2x0 C. was added oxalyl chloride (4.84 mL, 55.5 mmol) dropwise. The reaction mixture was allowed to warm to rt and stirring continued for 4 hours before Et3N (35 mL) and MeOH (10 mL) were added. The mixture was washed with water, brine, and dried over MgSO4. The crude keto ester was used directly in the next step.
Step 6: To the keto ester in THF (300 mL) was added BH3.Me2S (10 M, 36 mL) dropwise at rt and the reaction mixture was refluxed overnight. The mixture was cooled at 0xc2x0 C. before NaOH (30%, 150 mL) was added and stirring continued for 30 min. THF was removed under reduced pressure and the reaction mixture was extracted with EtOAc, washed with water, brine, and dried over MgSO4. Purification on column chromatography (15 to 20% EtOAc/hexanes) yielded the desired product as a white solid (15.9 g, 24.7 mmol, 58% over 3 steps).
Step 7: To a solution of oxalyl chloride (0.372 mL, 4.27 mmol) in CH2Cl2 (10 mL) at xe2x88x9278xc2x0 C. was added DMSO (0.661 mL, 9.31 mmol) dropwise. The reaction mixture was stirred at the same temperature for 5 min before a solution of 2-{1-benzhydryl-2-[2-(tert-butyl-diphenyl-silanyloxy)-ethyl]-5-chloro-1H-indol-3-yl}ethanol (2.50 g, 3.88 mmol) in CH2Cl2 (8 mL) was introduced. After additional 40 min stirring, iPr2NEt (3.38 mL, 19.4 mmol) was added and the reaction was quenched with cold water (5 mL) and extracted with CH2Cl2. The organic layer was dried over MgSO4 and evaporated. The crude {1-Benzhydryl-2-[2-(tert-butyl-diphenyl-silanyloxy)-ethyl]-5-chloro-1H-indol-3-yl}-acetaldehyde was used directly in the next step.
Step 8: To a solution of the crude aldehyde (3.88 mmol) in 1,2-dichloroethane (39 mL) at 0xc2x0 C. were added methyl 4-aminobenzoate (645 mg, 4.27 mmol), acetic acid (1.33 mL), and NaBH(OAc)3. The reaction mixture was allowed to warm to rt overnight and quenched with cold NaHCO3. An extractive workup furnished the desired 4-(2-{1-Benzhydryl-2-[2-(tert-butyl-diphenyl-silanyloxy)-ethyl]-5-chloro-1H-indol-3-yl}-ethylamino)-benzoic acid methyl ester which was used directly in the next step without further purification.
Step 9: To 4-(2-{1-benzhydryl-2-[2-(tert-butyl-diphenyl-silanyloxy)-ethyl]-5-chloro-1H-indol-3-yl}-ethylamino)-benzoic acid methyl ester (3.88 mmol) in THF (25 mL) at 0xc2x0 C. was added a mixture of HOAc:1M TBAF (in THF) (2.3 mL:5.8 mL) and the reaction mixture was allowed to stir at rt for 18 h. Extractive workup followed by trituration with 5%EtOAc/hex gave the desired 4-{2-[1-Benzhydryl-5-chloro-2-(2-hydroxy-ethyl)-1H-indol-3-yl]-ethylamino}-benzoic acid methyl ester with slight impurity as an off-white solid (92%, over 3 steps).
Step 10: To a solution of 4-{2-[1-benzhydryl-5-chloro-2-(2-hydroxy-ethyl)-1H-indol-3-yl]-ethylamino)benzoic acid methyl ester (1.64 g, 3.04 mmol) in CH2Cl2 at 0xc2x0 C. were added Et3N (0.636 mL, 4.56 mmol) and MsCl (0.282 mL, 3.64 mmol). After stirring at the same temperature for 35 min, the reaction mixture was quenched with cold water. An extractive workup revealed the crude mesylate as an off-white solid (1.70 g, 90%).
Step 11: A solution of the crude mesylate (1.70 g, 2.75 mmol) and NaN3 (89 mg, 13.8 mmol) in DMF (14 mL) was stirred at 80xc2x0 C. for 6 h. The reaction mixture was diluted with EtOAc and subjected to an aqueous workup followed by flash column chromatography to yield the desired 4-{2-[2-(2-Azido-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-ethylamino}-benzoic acid methyl ester (813 mg, 52% yield).
Step 12: To 4-{2-[2-(2-azido-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-ethylamino}-benzoic acid methyl ester (400 mg, 0.709 mmol) in THF (4 mL) at 0xc2x0 C. was added Ph3P (223 mg, 0.851 mmol) in portions. The reaction mixture was stirred at rt for 11 h and 35xc2x0 C. for 4 h before water (50 uL) was added and stirring continued overnight. The reaction mixture was diluted with EtOAc, dried with MgSO4 and purified by flash column chromatography (EtOAc to 20%MeOH/EtOAc with 1% Et3N) to give the desired 4-{2-[2-(2-Amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-ethylamino}-benzoic acid methyl ester (201 mg, 53%) as a solid.
Synthesis of Intermediate No. 4 is also described below in Example 142, Steps 1-12.
Intermediate No. 5
4-({2-[2-(2-Amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-ethyl}-methyl-amino)-benzoic acid methyl ester 
Step 1: Crude {1-Benzhydryl-2-[2-(tert-butyl-diphenyl-silanyloxy)-ethyl]-5-chloro-1H-indol-3-yl}-acetaldehyde from Intermediate No. 4 synthesis Step 7 was treated with 4-Methylamino-benzoic acid methyl ester according to the procedure in Intermediate No. 4 step 8 to yield the desired 4-[(2-{1-Benzhydryl-2-[2-(tert-butyl-diphenyl-silanyloxy)-ethyl]-5-chloro-1H-indol-3-yl}-ethyl)-methyl-amino]-benzoic acid methyl ester in 73% yield.
Step 2: The title compound was prepared according to the procedure described for Intermediate No 4 step 9. The crude 4-({(2-[1-Benzhydryl-5-chloro-2-(2-hydroxy-ethyl)-1H-indol-3-yl]-ethyl}methyl-amino)-benzoic acid methyl ester was used in the next step directly without further purification.
Step 3-6: 4-({2-[2-(2-Azido-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-ethyl}-methyl-amino)-benzoic acid methyl ester was prepared according to the procedure described for Intermediate No. 4 steps 10-12 in 61% (3 steps).
Step 7: A solution of 4-({2-[2-(2-azido-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-ethyl}methyl-amino)-benzoic acid methyl ester (410 mg, 0.709 mmol) and 10% Pd/C (155 mg) in MeOH:CH2Cl2(=7 mL:1 mL) was stirred under H2 atmosphere (1 atm) for 2h15 min. The reaction mixture was filtered through celite and rinsed with MeOH and CH2Cl2. Flash column chromatography (CH2Cl2to 8% MeOH/CH2Cl2) of the residue gave the desired 4-({2-[2-(2-Amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-ethyl}-methyl-amino)-benzoic acid methyl ester in 78% yield (305 mg).
Synthesis of Intermediate No. 5 is also described below in Example 146, Steps 1-7.
The compounds of this invention may be used as intermediates in the synthesis of pharmaceutically useful compounds of formula V: 
wherein:
X is a linking group selected from of xe2x80x94Oxe2x80x94, xe2x80x94CH2xe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94NHxe2x80x94, and xe2x80x94N(C1-C6-alkyl)xe2x80x94;
R1, R2, R3, R4, R5 and R6 are each independently selected from H, halogen, xe2x80x94CN, xe2x80x94CHO, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94OH, xe2x80x94C1-C6 alkyl, C1-C6 alkoxy, xe2x80x94NH2, xe2x80x94N(C1-C6)2, xe2x80x94NH(C1-C6), xe2x80x94Nxe2x80x94C(O)xe2x80x94(C1-C6), xe2x80x94NO2, or a 5- or 6-membered heterocyclic or heteroaromatic ring containing 1 or 2 heteroatoms selected from O, N or S;
R7 and R8 are independently selected from H, halogen, xe2x80x94CN, xe2x80x94CHO, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94OH, xe2x80x94C1-C6 alkyl, C1-C6 alkoxy, C1-C6 thioalkyl, xe2x80x94NH2, xe2x80x94N(C1-C6)2, xe2x80x94NH(C1-C6), xe2x80x94Nxe2x80x94C(O)xe2x80x94(C1-C6), or xe2x80x94NO2;
R9 is the formula xe2x80x94(CH2)n4xe2x80x94CO2H or a pharmaceutically acceptable acid mimic or mimetic, as defined above;
R10 is selected from H, halogen, xe2x80x94CN, xe2x80x94CHO, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94OH, xe2x80x94C1-C6 alkyl, C1-C6 alkoxy, C1-C6 thioalkyl, xe2x80x94NH2, xe2x80x94N(C1-C6)2, xe2x80x94NH(C1-C6), xe2x80x94Nxe2x80x94C(O)xe2x80x94(C1-C6), or xe2x80x94NO2;
R11 is selected from H, halogen, xe2x80x94CN, xe2x80x94CHO, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94OH, xe2x80x94C1-C6 alkyl, C1-C6 alkoxy, C1-C6 thioalkyl, xe2x80x94NH2, xe2x80x94N(C1-C6)2, xe2x80x94NH(C1-C6), xe2x80x94Nxe2x80x94C(O)xe2x80x94(C1-C6), xe2x80x94NO2, xe2x80x94Nxe2x80x94C(O)xe2x80x94N(C1-C3 alkyl)2, xe2x80x94Nxe2x80x94C(O)xe2x80x94NH(C1-C3alkyl), xe2x80x94Nxe2x80x94C(O)xe2x80x94Oxe2x80x94(C1-C3 alkyl), xe2x80x94SO2xe2x80x94C3-C6 alkyl, xe2x80x94Sxe2x80x94C3-C6 cycloalkyl, xe2x80x94Sxe2x80x94CH2xe2x80x94C3-C6 cycloalkyl, xe2x80x94SO2-C3-C6 cycloalkyl, xe2x80x94SO2xe2x80x94CH2xe2x80x94C3-C6 cycloalkyl, C3-C6 cycloalkyl, xe2x80x94CH2xe2x80x94C3-C6 cycloalkyl, xe2x80x94Oxe2x80x94C3-C6 cycloalkyl, , xe2x80x94Oxe2x80x94CH2xe2x80x94C3-C6 cycloalkyl, phenyl, benzyl, benzyloxy, morpholino or other heterocycles such as pyrrolidino, piperidine, piperizine furan, thiophene, imidazole, tetrazole, pyrazine, pyrazolone, pyrazole, imidazole, oxazole or isoxazole, the rings of each of these R4 groups each being optionally substituted by from 1 to 3 substituents selected from the group of H, halogen, xe2x80x94CN, xe2x80x94CHO, xe2x80x94CF3, xe2x80x94OH, xe2x80x94C1-C6 alkyl, C1-C6 alkoxy, xe2x80x94NH2, xe2x80x94N(C1-C6)2, xe2x80x94NH(C1-C6), xe2x80x94Nxe2x80x94C(O)xe2x80x94(C1-C6), xe2x80x94NO2, SO2(C1-C3 alkyl), xe2x80x94SO2NH(C1-C3 alkyl), xe2x80x94SO2N(C1-C3 alkyl)2, or OCF3;
n, is an integer from 1 to 3;
n2 is an integer from 0 to 4;
X1 is selected from a chemical bond, xe2x80x94Sxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94S(O)xe2x80x94, xe2x80x94S(O)2xe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94NHC(O)xe2x80x94, xe2x80x94Cxe2x95x90Cxe2x80x94
R12 is a ring moiety selected from C1-C6 alkyl, C1-C6 fluorinated alkyl, C3-C6 cycloalkyl, tetrahydropyranyl, camphoryl, adamantyl, CN, xe2x80x94N(C1-C6 alkyl)2, phenyl, pyridinyl, pyrimidinyl, furyl, thienyl, napthyl, morpholinyl, triazolyl, pyrazolyl, piperidinyl, pyrrolidinyl, imidazolyl, piperizinyl, thiazolidinyl, thiomorpholinyl, tetrazole, indole, benzoxazole, benzofuran, imidazolidine-2-thione, 7,7-dimethyl-bicyclo[2.2.1]heptan-2-one or pyrrolyl groups, each optionally substituted by from 1 to 3, preferably 1 to 2, substituents independently selected from H, halogen, xe2x80x94CN, xe2x80x94CHO, xe2x80x94CF3, xe2x80x94OH, xe2x80x94C1-C6 alkyl, C1-C6 alkoxy, xe2x80x94NH2, xe2x80x94N(C1-C6)2, xe2x80x94NH(C1-C6), xe2x80x94Nxe2x80x94C(O)xe2x80x94(C1-C6), xe2x80x94NO2, xe2x80x94SO2(C1-C3 alkyl), xe2x80x94SO2NH2, xe2x80x94SO2NH(C1-C3 alkyl), xe2x80x94SO2N(C1-C3 alkyl)2, OCF3, xe2x80x94COOH, xe2x80x94CH2xe2x80x94COOH, xe2x80x94CH2xe2x80x94N(C1-C6 alkyl), xe2x80x94CH2xe2x80x94N(C1-C6 alkyl)2, xe2x80x94CH2xe2x80x94NH2, pyridine or 
or a pharmaceutically acceptable salt or ester form thereof.
Among the more preferred ester forms of the compounds of formula V wherein R9 is the formula xe2x80x94(CH2)n4xe2x80x94CO2H, are the C1-C8 alkyl esters, including straight, branched or cyclic alkyl groups, or benzyl esters.
The final pharmaceutically useful compounds of formula V, which may be prepared using the intermediate compounds of this invention, inhibit cPLA2 activity which is required for supplying arachidonic acid substrate to cyclooxygenase-1 or -2 and 5-lipoxygenase which in turn initiate the production of prostaglandins and leukotrienes respectively. In addition, cPLA2 activity is essential for producing the lyso-phospholipid that is the precursor to PAF. Thus the final compounds are useful in the treatment and prevention of disease states in which leukotrienes, prostaglandins or PAF are involved. Moreover, in diseases where more than one of these agents plays a role, a cPLA2 inhibitor would be expected to be more efficacious than leukotriene, prostaglandin or PAF receptor antagonists and also more effective than cyclooxygenase or 5-lipoxygenase inhibitors.
Therefore, the compounds of formula V, pharmaceutical compositions containing these compounds and methods of using such compounds described herein are useful in treating and preventing the disorders treated by cyclooxygenase-2, cycloxygenase-1, and 5-lipoxygenase inhibitors and also antagonists of the receptors for PAF, leukotrienes or prostaglandins. Diseases which may be treated include but are not limited to: pulmonary disorders including diseases such as asthma, chronic bronchitis, and related obstructive airway diseases; allergies and allergic reactions such as allergic rhinitis, contact dermatitis, allergic conjunctivitis, and the like; inflammation such as arthritis or inflammatory bowel diseases, skin disorders such as psoriasis, atopic eczema, acne, UV damage, bums and dermatittis; cardiovascular disorders such as atherosclerosis, angina, myocardial ischaemia, hypertension, platelet aggregation, and the like; and renal insufficiency induced by immunological or chemical. The compounds of formula V may also be cytoprotective, preventing damage to the gastrointestinal mucosa by noxious agents. These compounds will also be useful in the treatment of adult respiratory distress syndrome, endotoxin shock and ischeamia induced injury including myocardial or brain injury.
These compounds, compositions and methods will be especially useful in the treatment of arthritic disorders, including but not limited to rheumatoid arthritis, spondyloarthropathies, gouty arthritis, osteoarthritis, systemic lupus erythematosus and juvenile arthritis, and also in the treatment of post- operative inflammation including that following ophthalmic surgery such as cataract surgery or refractive surgery.
The pharmaceutical agents described above can be used as antipyretic agents. They may be utilized in methods of treating pain, particularly the pain associated with inflammation.
Compounds of formula V and pharmaceutically acceptable compositions thereof are useful in the treatment of menstrual cramps, pre-term labor, tendonitis, bursitis, allergic neuritis, cytomegalovirus infection, apoptosis, including HIV-induced apoptosis, lumbago, liver disease including hepatitis. They are also useful in treating gastrointestinal conditions such as inflammatory bowel disease, Crohn""s disease, gastritis, irritable bowel syndrome and ulcerative colitis and for the prevention of treatment of cancer such as colorectal cancer. The pharmaceutical compounds and compositions described herein are also useful for the prevention or treatment of benign and malignant tumors/neoplasia including cancers such as colorectal cancer, brain cancer, bone cancer, epithelial cell-derived neoplasia (epithelial carcinoma) such as basal cell carcinoma, adenocarcinoma, gastrointestinal cancer, including lip cancer, mouth cancer, esophogeal cancer, small bowel cancer and stomach cancer, colon cancer, liver cancer, bladder cancer, pancreatic cancer, ovarian cancer, cervical cancer, lung cancer, breast cancer, and skin cancers, such as squamous cell and basal cell cancers, prostate cancer, renal cell carcinoma, and other known cancers that effect epithelial cells throughout the body. Neoplasias for which these compositions are contemplated to be particularly useful are gastrointestinal cancer, Barrett""s esophagus, liver cancer, bladder cancer, pancreas cancer, ovarian cancer, prostatic cancer, cervical cancer, lung cancer, breast cancer, and skin cancer, such as squamous cell and basal cell cancers. The compounds and methods can also be used to treat the fibrosis occurring with radiation therapy. Such compositions can be used to treat subjects having adenomatous polyps, including those with familial adenomatous polyposis (FAP). Additionally, such compositions can be used to prevent polyps from forming in patients at risk of FAP. Compounds of this invention are useful in the treatment of cancers because of their anti-angiogenic effects.
The novel intermediate compounds of formula I and the final pharmaceutically useful compounds of formula V may be prepared by various methods which are set forth generally and illustrated specifically in the following synthetic methods and specific examples. The following examples are presented to illustrate certain embodiments of the present invention, but should not be construed as limiting the scope of this invention. 
Method A
The initial indole of Method A may be alkylated at the C3 position with aldehydes or the corresponding acetals in the presence of a Lewis or Bronsted acid, such as boron triflouride etherate or triflouroacetic acid. In the synthetic scheme, above, X is as defined herein and Ph refers to the corresponding phenyl ring optionally substituted by R7, R8 and R9. The indole nitrogen may then be alkylated by treatment with a strong base such as sodium bis(trimethylsilyl) amide, n-BuLi, sodium hydride or potassium hydride in a solvent such as DMF, DMSO or THF followed by exposure to the appropriate alkyl halide. The resulting product can be treated with carbon tetrabromide in carbon tetrachloride and a catalytic amount of benzoyl peroxide to effect dibromination of the C2 methyl group. The dibromide can then either be stirred with silver carbonate in acetone water or poured into DMSO and stirred. Both of these procedures generate the aldehyde which is then subjected to the nitro aldol reaction with nitromethane and a catalytic amount of ammonium acetate at reflux. The resulting vinyl nitro intermediate is reduced to the amine upon treatment with zinc mercury amalgam in a mixture of THF and conc. HCL at reflux. This amine can then be treated with the requisite sulfonyl chloride under biphasic conditions, aqueous sodium bicarbonate/dichloromethane, or in organic solvent with the addition of a hindered organic amine base. The final hydrolysis was accomplished under basic conditions with sodium hydroxide in water and methanol and THF at room temperature or at elevated temperature. Alternatively it may be cleaved by treatment with sodium thiomethoxide in a solvent such as THF or DMF at elevated temperatures (50xc2x0 C.-100xc2x0 C.). This method was used in the synthesis of Examples 1-887, 108-112, and 126-128. 
Method B
The initial halide of Method B is refluxed in aqueous sodium sulfite and a suitable cosolvent if necessary, such as alcohol, dioxane etc, for the required amount of time to form the desired sodium sulfonate. This intermediate was treated with thionyl chloride, phosphorous pentachloride or oxalyl chloride, in dichloromethane with a small amount of DMF and stirred for several hours at room temperature until the sulfonyl chloride is formed. The thus formed sulfonyl chloride is then used crude in Method A. This method was used in the synthesis of Examples 1-887, 108-112 and 126-128 when the sulfonyl chloride was not commercially available.